PROJECT SUMMARY &#61538;cell proliferation is high during perinatal stages, but declines precipitously prior to adulthood, due in part to increased expression of cell cycle inhibitors with age. Insulin resistant states, such as pregnancy and obesity, stimulate replication in adult &#61538;cells that are normally quiescent. &#61472;Failure to increase &#61538;cell mass can lead to Type 2 diabetes or gestational diabetes (GDM). The FoxM1 transcription factor is expressed in proliferating cells and promotes cell cycle progression. We showed that mice lacking FoxM1 in their pancreas became diabetic as adults due to a failure of &#61538;cell mass expansion after four weeks of age. We also showed that FoxM1 is critical for &#61538;cell regeneration and replication following pancreatic injury, high fat diet, and during pregnancy. The major pregnancy hormone, placental lactogen (PL), induced Foxm1 expression and FoxM1 was required for PL-induced &#61538;cell replication. We hypothesize that FoxM1 represents a nodal point at which all stimulatory pathways for &#61538;cell proliferation intersect, and that FoxM1 function becomes limiting in adult &#61538;cells, resulting in decreased proliferative capacity. We will test these hypotheses using in vitro and in vivo approaches. In isolated islets, we will determine the second messenger signaling pathways that induce Foxm1 transcription. Using existing p16 and p27 mutant mice, we will determine whether these cell cycle inhibitors that are normally repressed by FoxM1 expression, are the main effectors of FoxM1 inactivation, resulting in failed &#61538;cell replication even under stimulatory conditions. In addition, we will determine whether &#61538;cell-specific expression of activated FoxM1 in vivo (using an inducible transgene) can increase replication of adult &#61538;cells and restore rates of proliferation seen in younger animals. A thorough understanding of how FoxM1 functions to regulate &#61538;cell replication will lead to strategies for enhancing &#61538;cell proliferation for the treatment of diabetes.